Process for preparing secondary alcohol

Abstract

 A process for preparing a secondary alcohol which is characterized by adding a primary or a secondary amine to the reaction system in the case that the secondary alcohol is prepared by hydrogenating, in the presence of a noble metal, an epoxy derivative represented by the following formula,

   wherein R¹ and R² are the same or different, an organic group not containing an aldehyde group or keto group therein or a hydrogen atom, provided that both R¹ and R² are not simultaneously a hydrogen atom.

Description

[0001] The present invention relates to a novel process for preparing a secondary alcohol which is useful as an intermediate for synthesizing medicines such as antiarrhythmic drugs, physiologically active compounds or functional materials such as liquid crystals.

[0002] An optically active medicine or its intermediate is generally required to have high chemical and optical purity. Therefore, it is a very important problem to establish a process for preparing an optically active secondary alcohol with high chemical and optical purity.

[0003] As one of the methods for preparing an optically active secondary alcohol, it is known that an optically active secondary alcohol is prepared by hydrogenating an optically active 1,2-epoxide in the presence of a palladium catalyst. According to this method, there is obtained not only an object secondary alcohol, but also its position isomer, a primary alcohol. In order to prevent the production of a primary alcohol, various studies have been done.

[0004] For example, the following methods (a) to (d) are reported.

(a) The reaction is carried out in the presence of sodium hydroxide in catalytic amount (Lisa M. SCHULTZE et al., Tetrahedron Lett., Vol. 39, p1853-1856 (1998)).

(b) The reaction is carried out in the coexistence of ammonium formate (Peter S. DRAGOVICH et al., J. Org. Chem., Vol.60, p4922-4924 (1995)).

(c) The reaction is carried out in the presence of a palladium-ethylenediamine complex as catalyst (Hironao SAJIKI et al., Chem. Commun., p1041-1042 (1999)).

(d) The reaction is carried out in the coexistence of a borane-tert-butylamine complex (Michel COUTURIER et al., Tetrahedron Lett., Vol.42, p2763-2766 (2001)).

[0005] In case of above method (a), it is possible to prevent the production of a primary alcohol, but the corresponding ketone is prepared in the course of the reaction. As many of the ketones are similar to the object secondary alcohol in boiling point, they are hardly separated and isolated by usual separation methods such as distillation.

[0006] In case of above method (b), an excess amount of ammonium formate is required. In case of above methods (c) and (d), the respective amine complex must be previously prepared.

[0007] Therefore, it is an object of the invention to provide a process for preparing a secondary alcohol improved from the view point of industrial production.

[0008] This object could be achieved on the basis of the finding that when preparing a secondary alcohol by hydrogenating a 1,2-epoxy derivative in the presence of a palladium catalyst, only by adding thereto a small amount of an amine, production of not only a primary alcohol, but also the corresponding alkane and ketone as by-products, is prevented and that the object secondary alcohol is prepared in a mild condition with high chemical and optical purity.

[0009] The present invention relates to a process for preparing a secondary alcohol represented by the following formula,

   wherein R¹ and R² are the same or different, an organic group not containing an aldehyde group or ketone group therein, or a hydrogen atom, provided that R¹ is not a hydrogen atom,
or the following formula,

   wherein R¹ and R² are the same as defined above, provided that R² is not a hydrogen atom,
which is characterized by adding a primary amine or a secondary amine to the reaction system in the case that the secondary alcohol (2) or (3) is prepared by hydrogenating, in the presence of a noble metal, an epoxide derivative represented by the following formula,

   wherein R¹ and R² are the same as defined above, provided that both R¹ and R² are not simultaneously a hydrogen atom.

[0010] The present invention preferably relates to a process for preparing a secondary alcohol represented by the following formula,

   wherein R^1a and R^2a are the same or different, a hydrogen atom, an optionally unsaturated C1-10 alkyl group, halogeno C1-10 alkyl group, optionally saturated C3-10 cycloalkyl group, C6-14 aryl group, aralkyl group, hydroxy substituted C1-10 alkyl group, C1-10 alkyloxy substituted C1-10 alkyl group, furyl substituted C1-10 alkyl group, or aryloxy substituted C1-10 alkyl group, provided that R^1a and R^2a are not simultaneously a hydrogen atom,
or the following formula;

   wherein R^1a and R^2a are the same as defined above, provided that R^2a is not a hydrogen atom,
which is characterized by adding a primary amine or a secondary amine to the reaction system in the case that the secondary alcohol (2a) or (3a) is prepared by hydrogenating, in the presence of a noble metal, an epoxy derivative represented by the following formula,

   wherein R^1a and R^2a are the same as defined above, provided that both R¹ and R² are not simultaneously a hydrogen atom.

[0011] According to the present invention, when an epoxy derivative (1) or (1a) is used in the optically active form, the objective optically active secondary alcohol can be obtained in high chemical purity without racemization.

[0012] The principle to prevent the production of a ketone compound as a by-product consists in converting a produced ketone compound into an amine compound chemically and physically different from the ketone compound by adding a primary or secondary amine. By doing so, the purification of the objective secondary alcohol becomes easy and it becomes possible to obtain the secondary alcohol in higher purity which is required e.g. in the field of manufacture of medicines.

[0013] Although reductive amination of a ketone compound in the presence of a noble metal such as palladium or platinum is known, the present invention wherein a secondary alcohol in higher purity is obtainable by coexistence of this reaction together with the hydrogenation reaction of an epoxy derivative, has not been reported and is a novel finding.

[0014] The epoxy derivative (1) or (1a) used in this reaction may be a commercially available one or one which is otherwise obtainable e.g. by cyclization of a halohydrin derivative or oxidation of an olefine compound.

[0015] The substituents R¹ and R² in the formula (1) are not limited except for a group which inhibits the present reaction such as an aldehyde group or keto group therein, or a group which is affected by the present reaction and as far as the secondary alcohol is producible as a reaction product. Substituents R¹ and R² may be the same or different.

[0016] Preferable substituents of R^1a and R^2a in the formula (1a) are an unsaturated C1-10 alkyl group such as a hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, n-decyl group, allyl group, 3-butenyl group or 5-hexenyl group; halogeno C1-10 alkyl group such as a monochloromethyl group;, optionally saturated C3-10 cycloalkyl group such as a cyclohexyl group or 1-cyclohexenyl group; C6-14 aryl group such as phenyl group or naphthyl group; aralkyl group such as a benzyl group, phenethyl group or cinnamyl group; hydroxy substituted C1-10 alkyl group such as a hydroxymethyl group; C1-10 alkyloxy substituted C1-10 alkyl group such as a methoxymethyl group; furyl substituted C1-10 alkyl group such as a furfuryl group; and aryloxy substituted C1-10 alkyl group such as aphenoxymethyl group. More preferably R^1a is a C1-10 straight or branched alkyl group, or C6-10 aryl group, and R^2a is a hydrogen atom. Especially preferable compounds of the formula (1a) are 1,2-epoxybutane, 1,2-epoxypentane, 1,2-epoxyhexane and 1,2-epoxyoctane.

[0017] The amines used in the present invention are not limited as long as the amines can reductively aminate the ketones produced as by-product, such as a primary amine, e.g., methylamine, ethylamine, allylamine, n-butylamine, isobutylamine, tert-butylamine, cyclohexylamine, aniline, benzylamine and ethylenediamine, a secondary amine, e.g., dimethylamine, diethylamine, diisopropylamine, dicyclohexylamine, pyrrrolidine, piperidine and morpholine. The amount of the amine is theoretically equimolar with the ketone produced as by-product, and preferably 0.01 to 1 mole, more preferably 0.01 to 0.2 mole, most preferably 0.01 to 0.12 mole, to an epoxy derivative (1) or (1a).

[0018] The noble catalyst used in the present invention includes catalysts supporting a noble metal such as palladium or platinum on a carrier such as carbon, alumina, silica, zeolite, an alkaline earth metal carbonate or a non-supported noble metal, an oxidized noble metal alone, or a mixture thereof. These may be a dried or wet form.

[0019] In the present invention, when the epoxy derivative (1) or (1a) is solid, the reaction is carried out in an organic solvent wherein it can dissolve, and when it is a liquid, the reaction can be carried out in an organic solvent or without any solvent. The organic solvent unlimitedly includes an alcohol-solvent such as methanol, ethanol and 2-propanol, an ester-solvent such as ethyl acetate and butyl acetate, an ether-solvent such as ethyl ether and tert-butylmethyl ether, a halogeno compound-solvent such as chloroform and 1,2-dichloroethane, and a hydrocarbon-solvent such as toluene and n-hexane. The amount of the organic solvent is suitably 0.5 to 40 (w/w) times as much as the amount of the epoxide derivative (1) or (1a).

[0020] The merits of the present invention consists in obtaining an objective secondary alcohol in high purity with a very simple method such as a conventional purification method, e.g., distillation or chromatography, without using the rectification which requires high techniques. Furthermore, when using an optically active epoxy derivative, the corresponding optically active secondary alcohol can be obtainable without racemization.

[0021] The present invention is explained by the following examples, but the present invention should not be limited by these examples.

Example 1

2-Octanol

[0022] To a 50-ml reaction vessel were added 1,2-epoxyoctane (2.56g, 20.0mmol), methanol (18ml), 10% palladium/carbon containing 50% water (425mg, Pd: 0.20mmol) and a catalytic amount of an amine subsequently, and then the mixture was vigorously stirred under an atmosphere of hydrogen at 25°C. Twenty to forty hours later, 10% palladium/carbon was removed by filtration and methanol was removed by distillation. The selectivity of the obtained colorless oil was checked by gas chromatographic analysis. The results obtained by adding various amines and other additives were respectively shown as follows:

Table 1

	Additive (equiv.)	Production ratio (%)
		2-Octanol	1-Octanol	2-Octanone	Octane
Example 1-1	n-BuNH2 (0.01)	98	2	0	0
Example 1-2	Et2NH (0.10)	98	2	0	0
Comparative example 1	None	67	8	2	23
Comparative example 2	NaOH (0 .01)	95	1	3	1
Comparative example 3	Na2CO3 (0.01)	95	1	3	1
Comparative example 4	NaHCO3 (0.10)	94	1	4	1
Comparative example 5	AcONa (0.01)	95	1	3	1
Comparative example 6	AcONH4 (0.01)	96	2	2	0
Comparative example 7	Et3N (0.01)	95	2	3	0

Example 2

(S)-2-Hexanol

[0023] To a 1-liter reaction vessel were added (R)-1-chloro-2-hexanol (90.2g, 660mmol), methanol (110ml) and an aqueous 24%NaOH solution (132g, 792mmol), and the mixture was stirred at 10°C for 3 hours. Thereto was added an aqueous NaCl solution to separate with a separating funnel and the solvent was removed by distillation to give crude (R)-1,2-epoxyhexane. Thereto was added methanol (550ml), 10% palladium/carbon containing 50% water (14.0g) and n-butylamine (2.41g, 33mmol), and the mixture was vigorously stirred at 25°C under an atmosphere of hydrogen. Twenty hours later, 10% palladium/carbon was removed by filtration, and the filtrate was distilled to give objective (S)-2-hexanol (47.2g, yield: 70%, chemical purity: 99%, optical purity: 99%ee) as a colorless transparent oil.

[0024] Optical purity of the 2-hexanol is calculated on its area ratio by using gas chromatography after acetylation of the 2-hexanol.

Conditions

[0025] 

Column: CHIRALDEX G-TA by ASTEC Company (30m x 0.25mm I.D.)

Column temperature: 45°C

Sprit ratio: 100/1

Carrier gas: N₂ lml/min.

Retention time: (S) compound, 10.0 min., (R) compound, 10.8 min.

Example 3

(S)-2-Pentanol

[0026] To a 300-ml reaction vessel were added (R)-1,2-epoxypentane (38.8g, 450mmol), methanol (80mL), 5% palladium/carbon containing 55% water (3.88g) and n-butylamine (1.65g, 22.5mmol), and the mixture was vigorously stirred at 30°C under an atmosphere of hydrogen. Fifty hours later, 5% palladium/carbon was removed by filtration, and the filtrate was distilled to give objective (S)-2-pentanol (28.3g, yield: 71%, chemical purity: 99%, optical purity: 99%ee) as a colorless transparent oil.

[0027] The measurement of optical purity is carried out in the same manner as Example 2.
Retention time: (S) compound: 9.1 min., (R) compound: 10.3 min.

Example 4

(S)-2-Butanol

[0028] To a 300-ml reaction vessel (R)-1,2-epoxybutane (29.8g, 414mmol), 10% palladium/carbon containing 50% water (1.49g) and n-butylamine (1.51g, 20.7mmol), and the mixture was vigorously stirred at 30°C under an atmosphere of hydrogen. Thirty hours later, 10% palladium/carbon was removed by filtration and the filtrate was distilled to give objective (S)-2-butanol (18.4g, yield: 60%, chemical purity: 99%, optical purity: 99%ee) as a colorless transparent oil. The measurement of optical purity is carried out in the same manner as Example 2.
Retention time: (S) compound: 5.6 min., (R) compound: 6.1 min.

Claims

1. A process for preparing a secondary alcohol represented by the following formula,

   wherein R¹ and R² are the same or different, an organic group not containing an aldehyde group or keto group therein or a hydrogen atom, provided that R¹ is not a hydrogen atom,
or the following formula,

   wherein R¹ and R² are the same as defined above, provided that R² is not a hydrogen atom,
which is characterized by adding a primary amine or a secondary amine to the reaction system in the case that the secondary alcohol (2) or (3) is prepared by hydrogenating, in the presence of a noble metal, an epoxy derivative represented by the following formula,

   wherein R¹ and R² are the same as defined above, provided that both R¹ and R² are not simultaneously a hydrogen atom.

2. A process for preparing a secondary alcohol represented by the following formula (2a),

   wherein R^1a and R^2a are the same or different, a hydrogen atom, an optionally unsaturated C1-10 alkyl group, halogeno C1-10 alkyl group, optionally saturated C3-10 cycloalkyl group, C6-14 aryl group, aralkyl group, hydroxy substituted C1-10 alkyl group, C1-10 alkyloxy substituted C1-10 alkyl group, furyl substituted C1-10 alkyl group, or aryloxy substituted C1-10 alkyl group, provided that R^1a and R^2a are not simultaneously a hydrogen atom,
or the following formula,

   wherein R^1a and R^2a are the same as defined above, provided that R^2a is not a hydrogen atom,
which is characterized by adding a primary amine or a secondary amine to the reaction system in case that the secondary alcohol (2a) or (3a) is prepared by hydrogenating, in the presence of a noble metal, an epoxy derivative represented by the following formula,

   wherein R^1a and R^2a are the same as defined above, provided that both R¹ and R² are not simultaneously a hydrogen atom.

3. The process for preparing a secondary alcohol according to claim 1 or 2 wherein the epoxy derivative (1) or (1a) is an optically active compound.

4. The process for preparing a secondary alcohol or its optically active compound according to claim 2 wherein R^1a is a C1-10 alkyl or C6-14 aryl group and R^2a is a hydrogen atom in the epoxy derivative (1a) or its optically active compound.

5. The process for preparing a secondary alcohol according to any one of claims 1 to 4 wherein the noble metal catalyst is palladium.

6. The process for preparing a secondary alcohol according to any one of claims 1 to 5 wherein the epoxy derivative (1) or (1a) is 1,2-epoxybutane, 1,2-epoxypentane, 1,2-epoxyhexane or 1,2-epoxyoctane.